Relatively few studies have assessed the prospective relationship of sedentary lifestyle and coronary heart disease (CHD) in women. We performed a nested case-control study, identifying 50 cases of acute CHD in women and 150 age-matched controls. Risk factors including sedentary lifestyle, cigarette smoking, hypertension, diabetes mellitus, total, and HDL cholesterol levels had been previously determined in this cohort using household survey techniques. The odds ratio (OR) of CHD in sedentary women was 2.1 (95% CI 1.0-4.3, P = 0.046). The odds ratio was similar (OR = 2.3, 95% CI 1.0-5.7, P = 0.051) after adjusting for potential confounders of hypertension, cigarette smoking, low HDL cholesterol, diabetes mellitus, and being U.S. born. This study suggests that sedentary lifestyle may be an independent risk factor for CHD in women, but its results are open to several contradictory interpretations. Further studies to investigate the prospective relationship of sedentary lifestyle and the risk of CHD in women are needed.